1. Field of the Invention
The present invention relates to a process for preparing 3-chloromethyl-3-cefem derivatives expressed by Chemical Formula (6), which are useful as intermediates for synthesizing 3-chloromethyl-3-cephem antibiotics:
wherein R1 and R2 each represent an aromatic hydrocarbon group.
2. Description of the Related Art
The 3-chloromethyl-3-cefem derivatives expressed by Chemical Formula (6) are known as useful intermediates for synthesizing cephalosporin antibiotics, as disclosed in, for example, Japanese Unexamined Patent Application Nos. 59-172493, 58-72591, 60-255796, 61-5084, 1-156984, 1-308287.
For the preparation of a 3-chloromethyl-3-cephem derivative expressed by Chemical Formula (6), for example, a technique is disclosed in Development and Industrialization of New Intermediates 3-Chloromethyl-Δ3-Cephems for Cephalosporin Antibiotic Synthesis (Taniguchi et al., NIPPON KAGAKUKAISHI, No. 8, 577-587, 1995).
In particular, for the preparation of a 3-chloromethyl-3-cefem derivative expressed by Chemical Formula (9) from a chlorinated azetidinone derivative expressed by Chemical Formula (8), for example, Japanese Unexamined Patent Application No. 58-74689 has disclosed a process in which the chlorinated azetidinone derivative expressed by Chemical Formula (8) is allowed to react in an organic solvent in the presence of a base according to Reaction Formula (1).

However, the process proposed by Japanese Unexamined Patent Application No. 58-74689 provides 3-chloromethyl-3-cefem derivatives in an oil form. In this process, dimethylformamide, which dissolves both the starting material, an azetidinone derivative (Chemical Formula (8)), and the reaction product, a 3-chloromethyl-3-cephem derivative (Chemical Formula (9)), is used as a reaction solvent, and the starting material is allowed to react with a base, weak alkaline ammonia or ammonia water, while the reaction product is prevented from being decomposed.
In this process, an alcohol, such as methanol, ethanol, or 2-propanol, may be used as the reaction solvent, and a metal hydroxide, such as strongly basic sodium hydroxide or potassium hydroxide, may be used as the base. However, since the alcohol does not dissolve the reaction product, the 3-chloromethyl-3-cephem derivative, the use of the alcohol does not provide the reaction product in an oil form. In addition, the alcohol reacts with the base to produce water, which dissolves the base to increase the pH of the reaction system, that is, to make the reaction system alkaline. Consequently, the reaction product, the 3-chloromethyl-3-cephem derivative, is decomposed by the alkali and thus the yield is reduced.
Furthermore, 3-chloromethyl-3-cephem derivatives each include a high reaction activity chlorine atom in its molecule, and are, consequently, instable in an oil form. For example, the 3-chloromethyl-3-cephem derivatives release hydrochloric acid which causes self decomposition of the derivatives during storage at room temperature, thus degrading the quality.
Accordingly, a 3-chloromethyl-3-cephem derivative is desired that is relatively stable for a long time in moderate conditions.
A process has been proposed in which a crystalline 3-chloromethyl-3-cephem derivative is prepared.
For example, International Patent Application No. WO 99/10352 has proposed a process for preparing a crystalline 3-chloromethyl-3-cephem derivative by crystallizing an oily 3-chloromethyl-3-cephem derivative dissolved in dimethylformamide, with a solvent containing a cold alcohol.
However, this process includes a complicated step of crystallizing an oily 3-chloromethyl-3-cephem derivative that has once been synthesized, and is thus disadvantageous in industrial production.
Since a process for industrially preparing a crystalline 3-chloromethyl-3-cephem derivative expressed by Chemical Formula (6) includes a series of steps each using an expensive raw material, it is desired to recycle reaction by-products. In view of the above-mentioned disadvantages, therefore, the development of a series of preparing steps is required.